Project Summary Epidemiological studies indicate that aging is associated with a chronic increase in circulating levels of inflammatory molecules. Chronic inflammation has been linked to major aging-related changes and numerous aging-related chronic diseases, including diabetes. The overarching goal of this proposal is to elucidate the molecular and cellular mechanisms underlying aging-associated chronic inflammation and the development of diabetes. Nutritional status affects chronic inflammation, the rate of aging, and the development of aging related chronic diseases, suggesting a possible crosstalk between chronic inflammation regulated by physiological aging and nutritional status. We hypothesize that nutrient sensors regulate the inflammatory response pathways and provide a crosstalk between chronic inflammation regulated by physiological aging and nutritional status. This hypothesis is supported by our recent findings that a nutrient sensor regulates a key component of the inflammatory response pathway and is responsive to both physiological aging and nutritional status. We propose that the nutrient sensitive inflammatory response pathway forms the molecular interface between nutrient input and the metabolic network. Through this interface, cells can respond readily to metabolic and external cues, and dynamically regulate the metabolic status. Perturbation of this interface contributes to aging-associated chronic inflammation and diseases, such as diabetes. We have established mouse models to study chronic inflammation and metabolic perturbation during aging and overnutrition. We have also established a cell-based system to study aging- or overnutrition-associated inflammatory response in mechanistic details. Using the established system, we will elucidate the molecular events that result in increased chronic inflammation during aging or overnutrition. Using a gain-of-function approach, we will test the feasibility of activating these molecules to dampen aging or overnutrition-associated chronic inflammation and insulin resistance. Collectively, these studies highlight a novel nutrient sensitive inflammatory response pathway, which maintains metabolic homeostasis and is perturbed by overnutrition and physiological aging, thus is highly relevant to human health. The factors identified in our study are likely to play paramount roles in limiting chronic inflammation and suggest new approaches to combat chronic inflammation-related deterioration and diseases, such as diabetes.